Patients with pulmonary arterial hypertension (PAH) who carry a specific mutation in the RNF213 gene have poor clinical outcomes and worse response to combination treatments, according to a study from Japan.
A 2018 study found that approximately 10% of the patients with idiopathic PAH have a specific variant in the RNF213 gene — rs112735431, or p.Arg4810Lys — consisting of an amino acid substitution of arginine to lysine in the RNF213 protein. This gene alteration has already been associated with Moyamoya disease and peripheral pulmonary stenosis.
In the current study, the scientists set out to characterize and assess the outcomes of PAH patients with this variant.
A total of 139 patients with idiopathic or possibly heritable PAH were included, all treated between April 2005 and August 2018. Patients with mutations in the BMPR2 gene — with a well-known link to PAH — were included as controls.
At both diagnosis and after combination treatment with prostaglandin I2 (PGI2) infusion, endothelin receptor antagonists (ERAs), and/or phosphodiesterase-5 inhibitors (PDE5i), the patients underwent assessments of their serum levels of B-type natriuretic peptide (BNP) — a marker of heart failure and other cardiac problems — World Health Organization (WHO) class, and six-minute walk distance (6MWD), a test of exercise capacity.
Whole-exome sequencing, which screens the DNA bits containing information to generate a protein, found the p.Arg4810Lys variant in 11 patients (7.9% of the patients, eight women), all in only one of the gene copies (heterozygous). No patient showed cerebral involvement suggestive of Moyamoya disease.
All 11 patients had clinically severe disease at diagnosis, as indicated by their BNP levels, cardiac output, mean pulmonary arterial pressure (mPAP), and pulmonary vascular resistance (PVR). Eight were treated with PGI2.
Over a mean follow-up period of 30 months, both mPAP and PVR improved with combination treatment. In contrast, BNP levels, cardiac output, WHO class, and 6MWD scores did not change.
Two of these patients had both the studied variant in RNF213 and BMPR2 gene mutations, and did not respond favorably to treatment.
Compared with the 36 patients with BMPR2 gene mutations, the nine patients with the p.Arg4810Lys variant showed significantly inferior benefits with combination therapy, including in mPAP, cardiac output, BNP levels, and 6MWD scores. These patients also showed higher diastolic pressure gradients, suggesting worse response to treatment.
Four patients died, three of whom were in the group with the RNF213 gene variant. One patient in this group and two in the group with BMPR2 mutations underwent lung transplants. The RNF213 gene variant carrier who underwent this procedure experienced clinical improvements and did not require hospital admission for five years.
Event-free rates (no death or lung transplant) since diagnosis and the start of PGI2 treatment were significantly better in patients with BMPR2 mutations. Specifically, at five years after diagnosis, all patients with BMPR2 mutation survived and did not require lung transplants, compared with 60% in the RNF213 variant group.
After introduction of PGI2, none of the patients with the RNF213 variant were event-free, compared with 93% of controls who avoided these outcomes. A similar difference favoring the group without the variant in RNF213 was also found in terms of heart failure.
Patients with RNF213 variants other than p.Arg4810Lys showed better event-free rates after diagnosis than those with these gene alterations. A subsequent analysis showed that the p.Arg4810Lys variant was a risk factor for death, lung transplant, and heart failure.
Post-mortem analysis of lung samples from two patients with the p.Arg4810Lys variant found lesions in pulmonary arteries, and marked venous wall and arterial thickness, venous occlusion, dilated capillaries, and lymph accumulation.
“Patients with idiopathic PAH who have the RNF213 p.Arg4810Lys variant are associated with severe hemodynamics, poor reactivity to vasodilator drugs, and poor clinical outcomes,” the scientists wrote.
“Our findings may suggest the importance of genetic stratification of PAH to provide clinically relevant information for therapeutic strategies, leading to a personalized approach,” they added.
The researchers believe that earlier consideration of a lung transplant “might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH.”
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